In older adults with multi-morbidity, treatments targeting one disease may exacerbate co-occurring diseases or adversely affect overall health. Despite the potential for harm for the increasing numbers of individuals with multiple co-existing health conditions, this area has received little research attention. We explore the capability of using national population-based cohorts and novel analytical techniques to determine the harms and benefits of different treatment strategies across multiple disease-specific and health outcomes, particularly in situations in which the treatment of one condition may worsen another. We will use this innovative approach to investigate anti-hypertensive medication intensity in older adults with two commonly co-occurring conditions, namely hypertension and high fall/fracture risk. Modest, but conflicting, evidence suggests that anti-hypertensive medications may increase risk of falls, injuries, and other health outcomes in those at risk. Once we have tested the method with this important clinical question, we will extend to other sets of conditions and medications. This project builds on our ongoing work on tradeoffs among competing health conditions and mapping disease-specific outcomes onto overall, universal health outcomes. Specific aims are to test the hypotheses that, among comparable persons older adults with co- occurring hypertension and high fall/fracture risk, greater anti-hypertensive intensity is associated with fewer CV events and lower mortality but more frequent serious fall injuries, worse symptoms, lower activity level, and greater disability than lower anti-hypertensive intensity. In secondary analyses, we will explore these aims in relevant subgroups defined by age, gender, race, and co-morbidity burden. We will also determine if blood pressure levels and changes confound the effects of anti-hypertensive medication intensity on the outcomes. Two national, population-based cohorts, the Medicare Current Beneficiary Survey and the Medical Expenditure Panel Survey will be studied (study sample 35,000-40,000). Both have a wealth of longitudinal participant-reported, medication, and claims/health care utilization data. This depth and breadth of data allows us to use innovative analytical techniques to assess the effect of treatments on disease-specific and universal health outcomes (e.g. disability, symptom burden, functional limitations, and death), accounting for propensity to receive the treatment and for other confounders. We propose a new paradigm for quantifying the harm and benefit of treatments in complex older persons with multiple conditions. If treatments such as anti-hypertensives cause benefit as well as harm across a range of outcome domains, then this information must be uncovered and must inform clinical decision-making. Our ultimate goal is to develop a method for determining the optimal treatments for older adults with multiple conditions that maximizes benefit and minimizes harm within the outcome domain(s) of highest priority for each patient. PUBLIC HEALTH RELEVANCE: Among persons with multiple chronic conditions, treatments for one condition may exacerbate co-occurring conditions or adversely affect overall health outcomes. We are exploring whether greater antihypertensive medication intensity in older adults with co-occurring hypertension and fall/fracture risk benefits cardiovascular outcomes but worsens fall injury outcomes, symptoms, disability, or activity levels. Study results can help determine the net benefit or harm of commonly recommended treatments among the growing number of older adults with multiple health conditions.